Advanced Review
Evolution of homeobox genes
Peter W. H. Holland,
Corresponding Author
Peter W. H. Holland
Department of Zoology, University of Oxford, OX1 3PS, UK
Department of Zoology, University of Oxford, OX1 3PS, UKSearch for more papers by this authorPeter W. H. Holland,
Corresponding Author
Peter W. H. Holland
Department of Zoology, University of Oxford, OX1 3PS, UK
Department of Zoology, University of Oxford, OX1 3PS, UKSearch for more papers by this authorConflict of interest: The author declares that he has no conflicts of interest.
Abstract
Many homeobox genes encode transcription factors with regulatory roles in animal and plant development. Homeobox genes are found in almost all eukaryotes, and have diversified into 11 gene classes and over 100 gene families in animal evolution, and 10 to 14 gene classes in plants. The largest group in animals is the ANTP class which includes the well-known Hox genes, plus other genes implicated in development including ParaHox (Cdx, Xlox, Gsx), Evx, Dlx, En, NK4, NK3, Msx, and Nanog. Genomic data suggest that the ANTP class diversified by extensive tandem duplication to generate a large array of genes, including an NK gene cluster and a hypothetical ProtoHox gene cluster that duplicated to generate Hox and ParaHox genes. Expression and functional data suggest that NK, Hox, and ParaHox gene clusters acquired distinct roles in patterning the mesoderm, nervous system, and gut. The PRD class is also diverse and includes Pax2/5/8, Pax3/7, Pax4/6, Gsc, Hesx, Otx, Otp, and Pitx genes. PRD genes are not generally arranged in ancient genomic clusters, although the Dux, Obox, and Rhox gene clusters arose in mammalian evolution as did several non-clustered PRD genes. Tandem duplication and genome duplication expanded the number of homeobox genes, possibly contributing to the evolution of developmental complexity, but homeobox gene loss must not be ignored. Evolutionary changes to homeobox gene expression have also been documented, including Hox gene expression patterns shifting in concert with segmental diversification in vertebrates and crustaceans, and deletion of a Pitx1 gene enhancer in pelvic-reduced sticklebacks. WIREs Dev Biol 2013, 2:31–45. doi: 10.1002/wdev.78
This article is categorized under:
- Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
- Early Embryonic Development > Development to the Basic Body Plan
- Comparative Development and Evolution > Body Plan Evolution
REFERENCES
- 1Burglin TR. Homeodomain subtypes and functional diversity. Subcell Biochem 2011, 52: 95–122.
- 2Zhong Y-F, Butts T, Holland PWH. HomeoDB: a database of homeobox gene diversity. Evol Dev 2008, 10: 516–518.
- 3Zhong Y-F, Holland PWH. HomeoDB2: functional expansion of a comparative homeobox gene database for evolutionary developmental biology. Evol Dev 2011, 13: 567–568.
- 4Mukherjee K, Brocchieri L, Burglin TR. A comprehensive classification and evolutionary analysis of plant homeobox genes. Mol Biol Evol 2009, 26: 2775–2794.
- 5Derelle R, Lopez P, Le Guyader H, Manuel M. Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes. Evol Dev 2007, 9: 212–219.
- 6Shepherd JCW, McGinnis W, Carrasco AE, Derobertis EM, Gehring WJ. Fly and frog homoeo domains show homologies with yeast mating type regulatory proteins. Nature 1984, 310: 70–71.
- 7Dave V, Zhao C, Yang F, Tung CS, Ma J. Reprogrammable recognition codes in Bicoid homeodomain-DNA interaction. Mol Cell Biol 2000, 20: 7673–7684.
- 8Rivera-Pomar R, Niessing D, Schmidt-Ott U, Gehring WJ, Jackle H. RNA binding and translational suppression by bicoid. Nature 1996, 379: 746–749.
- 9Mizutani Y, Kihara A, Igarashi Y. Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 2005, 390: 263–271.
- 10Pewzner-Jung Y, Ben-Dor S, Futerman AH. When do lasses (longevity assurance genes) become CerS (ceramide synthases)? Insights into the regulation of ceramide synthesis. J Biol Chem 2006, 281: 25001–25005.
- 11Mukherjee K, Burglin TR. Comprehensive analysis of animal TALE homeobox genes: new conserved motifs and cases of accelerated evolution. J Mol Evol 2007, 65: 137–153.
- 12Holland PWH, Booth HAF, Bruford EA. Classification and nomenclature of all human homeobox genes. BMC Biol 2007, 5: 47.
- 13Joyner A, Hanks M. The engrailed genes: evolution of function. Semin Dev Bio 1991, 2:435: 445.
- 14Plouhinec JL, Sauka-Spengler T, Germot A, Le Mentec C, Cabana T, Harrison G, Pieau C, Sire JY, Veron G, Mazan S. The mammalian Crx genes are highly divergent representatives of the Otx5 gene family, a gnathostome orthology class of orthodenticle-related homeogenes involved in the differentiation of retinal photoreceptors and circadian entrainment. Mol Biol Evol 2003, 20: 513–521.
- 15de Rosa R, Grenier JK, Andreeva T, Cook CE, Adoutte A, Akam M, Carroll SB, Balavoine G. Hox genes in brachiopods and priapulids and protostome evolution. Nature 1999, 399: 772–776.
- 16Graham A, Papalopulu N, Krumlauf R. The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 1989, 57: 367–378.
- 17Stock DW, Ellies DL, Zhao ZY, Ekker M, Ruddle FH, Weiss KM. The evolution of the vertebrate Dlx gene family. Proc Natl Acad Sci USA 1996, 93: 10858–10863.
- 18Canon S, Herranz C, Manzanares M. Germ cell restricted expression of chick nanog. Dev Dyn 2006, 235: 2889–2894.
- 19Ryan JF, Burton PM, Mazza ME, Kwong GK, Mullikin JC, Finnerty JR. The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes: evidence from the starlet sea anemone, Nematostella vectensis. Genome Biol 2006, 7: R64.
- 20Laughon A, Scott MP. Sequence of a Drosophila segmentation gene–protein-structure homology with DNA binding proteins. Nature 1984, 310: 25–31.
- 21Sebe-Pedros A, de Mendoza A, Lang BF, Degnan BM, Ruiz-Trillo I. Unexpected repertoire of metazoan transcription factors in the unicellular holozoan Capsaspora owczarzaki. Mol Biol Evol 2011, 28: 1241–1254.
- 22Burglin TR. Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucl Acids Res 1997, 25: 4173–4180.
- 23Burglin TR. The PBC domain contains a MEINOX domain: coevolution of Hox and TALE homeobox genes? Dev Genes Evol 1998, 208: 113–116.
- 24Takatori N, Butts T, Candiani S, Pestarino M, Ferrier D, Saiga H, Holland PWH. Comprehensive survey and classification of homeobox genes in the genome of amphioxus, Branchiostoma floridae. Dev Genes Evol 2008, 218: 579–590.
- 25Brooke NM, Garcia-Fernandez J, Holland PWH. The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature 1998, 392: 920–922.
- 26Chourrout D, Delsuc F, Chourrout P, Edvardsen RB, Rentzsch F, Renfer E, Jensen MF, Zhu B, de Jong P, Steele RE, et al. Minimal ProtoHox cluster inferred from bilaterian and cnidarian Hox complements. Nature 2006, 442: 684–687.
- 27Garcia-Fernandez J. Hox, ParaHox, ProtoHox: facts and guesses. Heredity 2004, 94: 145–152.
- 28Gehring WJ, Kloter U, Suga H. Evolution of the Hox Gene complex from an evolutionary ground state. Curr Top Dev Biol 2009, 88: 35–61.
- 29Putnam NH, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A, Terry A, Shapiro H, Lindquist E, Kapitonov VV, et al. Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 2007, 317: 86–94.
- 30Hui JHL, Holland PWH, Ferrier DEK. Do cnidarians have a ParaHox cluster? Analysis of synteny around a Nematostella homeobox gene cluster. Evol Dev 2008, 10: 725–730.
- 31Quiquand M, Yanze N, Schmich J, Schmid V, Galliot B, Piraino S. More constraint on ParaHox than Hox gene families in early metazoan evolution. Dev Biol 2009, 328: 173–187.
- 32Kamm K, Schierwater B, Jakob W, Dellaporta SL, Miller DJ. Axial patterning and diversification in the Cnidaria predate the Hox system. Curr Biol 2006, 16: 920–926.
- 33Schierwater B, Kamm K. The early evolution of Hox genes: a battle of belief? Adv Exp Med Biol 2010: 81–90.
- 34Larroux C, Fahey B, Degnan SM, Adamski M, Rokhsar DS, Degnan BM. The NK homeobox gene cluster predates the origin of Hox genes. Curr Biol 2007, 17: 706–710.
- 35Ryan J, Pang K, Program NCS, Mullikin J, Martindale M, Baxevanis A. The homeodomain complement of the ctenophore Mnemiopsis leidyi suggests that Ctenophora and Porifera diverged prior to the ParaHoxozoa. EvoDevo 2010, 1: 9.
- 36Monteiro AS, Schierwater B, Dellaporta SL, Holland PWH. A low diversity of ANTP class homeobox genes in Placozoa. Evol Dev 2006, 8: 174–182.
- 37Schierwater B, Kuhn K. Homology of hox genes and the zootype concept in early metazoan evolution. Mol Phylogenet Evol 1998, 9: 375–381.
- 38Srivastava M, Begovic E, Chapman J, Putnam NH, Hellsten U, Kawashima T, Kuo A, Mitros T, Salamov A, Carpenter ML, et al. The Trichoplax genome and the nature of placozoans. Nature 2008, 454: 955–960.
- 39Jakob W, Sagasser S, Dellaporta S, Holland PWH, Kuhn K, Schierwater B. The Trox-2 Hox/ParaHox gene of Trichoplax (Placozoa) marks an epithelial boundary. Dev Genes Evol 2004, 214: 170–175.
- 40Butts T, Holland PWH, Ferrier DEK. The urbilaterian super-Hox cluster. Trends Genet 2008, 24: 259–262.
- 41Coulier F, Popovici C, Villet R, Birnbaum D. MetaHox gene clusters. J Exp Zool 2000, 288: 345–351.
- 42Jagla K, Bellard M, Frasch M. A cluster of Drosophila homeobox genes involved in mesoderm differentiation programs. BioEssays 2001, 23: 125–133.
- 43Luke GN, Castro LF, McLay K, Bird C, Coulson A, Holland PWH. Dispersal of NK homeobox gene clusters in amphioxus and humans. Proc Natl Acad Sci USA 2003, 100: 5292–5295.
- 44Castro LFC, Holland PWH. Chromosomal mapping of ANTP class homeobox genes in amphioxus: piecing together ancestral genomes. Evol Dev 2003, 5: 459–465.
- 45Pollard SL, Holland PWH. Evidence for 14 homeobox gene clusters in human genome ancestry. Curr Biol 2000, 10: 1059–1062.
- 46Hui JHL, McDougall C, Monteiro AS, Holland PWH, Arendt D, Balavoine G, Ferrier DEK. Extensive chordate and annelid macrosynteny reveals ancestral homeobox gene organization. Mol Biol Evol 2012, 29: 157–165.
- 47Garcia-Fernandez J. The genesis and evolution of homeobox gene clusters. Nat Rev Genet 2005, 6: 881–892.
- 48Holland PWH, Hogan BLM. Expression of homeobox genes during mouse development: a review. Genes Dev 1988, 2: 773–782.
- 49Mallo M, Wellik DM, Deschamps J. Hox genes and regional patterning of the vertebrate body plan. Dev Biol 2010, 344: 7–15.
- 50Prince VE, Price AL, Ho RK. Hox gene expression reveals regionalization along the anteroposterior axis of the zebrafish notochord. Dev Genes Evol 1998, 208: 517–522.
- 51Krumlauf R. Mouse Hox genetic functions. Curr Opin Genet Dev 1993, 3: 621–625.
- 52Andrew DJ, Scott MP. Downstream of the homeotic genes. New Biol 1992, 4: 5–15.
- 53Enriquez J, Boukhatmi H, Dubois L, Philippakis AA, Bulyk ML, Michelson AM, Crozatier M, Vincent A. Multi-step control of muscle diversity by Hox proteins in the Drosophila embryo. Development 2010, 137: 457–466.
- 54Hoppler S, Bienz M. Specification of a single cell type by a Drosophila homeotic gene. Cell 1994, 76: 689–702.
- 55Holland PWH, Garcia-Fernandez J. Hox genes and chordate evolution. Dev Biol 1996, 173: 382–395.
- 56Fröbius AC, Matus DQ, Seaver EC. Genomic organization and expression demonstrate spatial and temporal Hox gene colinearity in the lophotrochozoan Capitella sp. I. PLoS ONE 2008, 3: e4004.
- 57Holland PWH. Major transitions in animal evolution: A developmental genetic perspective. Am Zool 1998, 38: 829–842.
- 58Holland PWH. Beyond the Hox: how widespread is homeobox gene clustering? J Anat 2001, 199: 13–23.
- 59Ashizawa S, Brunicardi FC, Wang XP. PDX-1 and the pancreas. Pancreas 2004, 28: 109–120.
- 60Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BLM, Wright CVE. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996, 122: 983–995.
- 61Arendt D, Technau U, Wittbrodt J. Evolution of the bilaterian larval foregut. Nature 2001, 409: 81–85.
- 62Hui JHL, Raible F, Korchagina N, Dray N, Samain S, Magdelenat G, Jubin C, Segurens B, Balavoine G, Arendt D, et al. Features of the ancestral bilaterian inferred from Platynereis dumerilii ParaHox genes. BMC Biol 2009, 7: 43.
- 63Samadi L, Steiner G. Conservation of ParaHox genes' function in patterning of the digestive tract of the marine gastropod Gibbula varia. BMC Dev Biol 2010, 10: 74.
- 64Mazet F, Amemiya CT, Shimeld SM. An ancient Fox gene cluster in bilaterian animals. Curr Biol 2006, 16: R314–R316.
- 65Shimeld SM, Boyle MJ, Brunet T, Luke GN, Seaver EC. Clustered Fox genes in lophotrochozoans and the evolution of the bilaterian Fox gene cluster. Dev Biol 2010, 340: 234–248.
- 66Suga H, Tschopp P, Graziussi DF, Stierwald M, Schmid V, Gehring WJ. Flexibly deployed Pax genes in eye development at the early evolution of animals demonstrated by studies on a hydrozoan jellyfish. Proc Natl Acad Sci 2010, 107: 14263–14268.
- 67Rajkovic A, Yan CN, Yan W, Klysik M, Matzuk MM. Obox, a family of homeobox genes preferentially expressed in germ cells. Genomics 2002, 79: 711–717.
- 68Zhong Y-F, Holland PWH. The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages. BMC Evol Biol 2011, 11: 169.
- 69MacLean JA, Wilkinson MF. The Rhox genes. Reproduction 2010, 140: 195–213.
- 70Clapp J, Mitchell LM, Bolland DJ, Fantes J, Corcoran AE, Scoffing PJ, Armour JAL, Hewitt JE. Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 2007, 81: 264–279.
- 71Leidenroth A, Hewitt JE. A family history of DUX4: phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUX gene. BMC Evol Biol 2010, 10: 364.
- 72Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, et al. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 1999, 236: 25–32.
- 73Vandeutekom JCT, Wijmenga C, Vantienhoven EAE, Gruter AM, Frants RR, Hewitt JE, Padberg GW, Vanommen GJB, Hofker MH. FSHD associated DNA rearrangements are due to deletions of integral copies of A3.2 KB tandemly repeated unit. Hum Mol Genet 1993, 2: 2037–2042.
- 74Booth HAF, Holland PWH. Annotation, nomenclature and evolution of four novel homeobox genes expressed in the human germ line. Gene 2007, 387: 7–14.
- 75Dehal P, Boore JL. Two rounds of whole genome duplication in the ancestral vertebrate. PLOS Biol 2005, 3: 1700–1708.
- 76Holland PWH, Garcia-Fernàndez J, Williams NA, Sidow A. Gene duplications and the origins of vertebrate development. Dev Suppl 1994, 1994: 125–133.
- 77Putnam NH, Butts T, Ferrier DEK, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu J-K, et al. The amphioxus genome and the evolution of the chordate karyotype. Nature 2008, 453: 1064–1071.
- 78Jaillon O, Aury JM, Brunet F, Petit JL, Stange-Thomann N, Mauceli E, Bouneau L, Fischer C, Ozouf-Costaz C, Bernot A, et al. Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype. Nature 2004, 431: 946–957.
- 79Taylor JS, Braasch I, Frickey T, Meyer A, Van de Peer Y. Genome duplication, a trait shared by 22,000 species of ray-finned fish. Genome Res 2003, 13: 382–390.
- 80Lundin LG. Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse. Genomics 1993, 16: 1–19.
- 81Garcia-Fernandez J, Holland PWH. Archetypal organization of the amphioxus Hox gene cluster. Nature 1994, 370: 563–566.
- 82Ohno S. Evolution by gene duplication. New York: Springer-Verlag; 1970.
- 83Holland PWH. Molecular biology of lancelets: insights into development and evolution. Isr J Zool 1996, 42: S247–S272.
- 84Holland PWH. More genes in vertebrates? J Struct Funct Genomics 2003, 3: 75–84.
- 85Hoegg S, Boore JL, Kuehl JV, Meyer A. Comparative phylogenomic analyses of teleost fish Hox gene clusters: lessons from the cichlid fish Astatotilapia burtoni. BMC Genomics 2007, 8: 317.
- 86Geant E, Mouchel-Vielh E, Coutanceau J-P, Ozouf-Costaz C, Deutsch JS. Are cirripedia hopeful monsters? Cytogenetic approach and evidence for a Hox gene cluster in the cirripede crustacean Sacculina carcini. Dev Genes Evol 2006, 216: 443–449.
- 87Mouchel-Vielh E, Rigolot C, Gibert JM, Deutsch JS. Molecules and the body plan: the Hox genes of Cirripedes (Crustacea). Mol Phylogenet Evol 1998, 9: 382–389.
- 88Furlong RF, Younger R, Kasahara M, Reinhardt R, Thorndyke M, Holland P. A degenerate ParaHox gene cluster in a degenerate vertebrate. Mol Biol Evol 2007, 24: 2681–2686.
- 89Aboobaker AA, Blaxter ML. Hox gene loss during dynamic evolution of the nematode cluster. Curr Bio 2003, 13: 37–40.
- 90Holland LZ, Albalat R, Azumi K, Benito-Gutierrez E, Blow MJ, Bronner-Fraser M, Brunet F, Butts T, Candiani S, Dishaw LJ, et al. The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res 2008, 18: 1100–1111.
- 91Holland PWH. From genomes to morphology: a view from amphioxus. Acta Zool 2010, 91: 81–86.
- 92Frischer LE, Hagen FS, Garber RL. An inversion that disrupts the Antennapedia gene causes abnormal structure and localization of RNAs. Cell 1986, 47: 1017–1023.
- 93Schneuwly S, Kuroiwa A, Gehring WJ. Molecular analysis of the dominant homeotic Antennapedia phenotype. EMBO J 1987, 6: 201–206.
- 94Kessel M, Balling R, Gruss P. Variations of cervical vertebrate after expression of a Hox-1.1 transgene in mice. Cell 1990, 61: 301–308.
- 95Burke AC, Nelson CE, Morgan BA, Tabin C. Hox genes and the evolution of vertebrate axial morphology. Development 1995, 121: 333–346.
- 96Gaunt SJ. Conservation in the hox code during morphological evolution. Int J Dev Biology 1994, 38: 549–552.
- 97Averof M, Patel NH. Crustacean appendage evolution associated with changes in Hox gene expression. Nature 1997, 388: 682–686.
- 98Liubicich DM, Serano JM, Pavlopoulos A, Kontarakis Z, Protas ME, Kwan E, Chatterjee S, Tran KD, Averof M, Patel NH. Knockdown of Parhyale Ultrabithorax recapitulates evolutionary changes in crustacean appendage morphology. Proc Natl Acad Sci USA 2009, 106: 13892–13896.
- 99Pavlopoulos A, Kontarakis Z, Liubicich DM, Serano JM, Akam M, Patel NH, Averof M. Probing the evolution of appendage specialization by Hox gene misexpression in an emerging model crustacean. Proc Natl Acad Sci USA 2009, 106: 13897–13902.
- 100Shashikant CS, Kim CB, Borbely MA, Wang WCH, Ruddle FH. Comparative studies on mammalian Hoxc8 early enhancer sequence reveal a baleen whale-specific deletion of a cis-acting element. Proc Natl Acad Sci USA 1998, 95: 15446–15451.
- 101Shapiro MD, Marks ME, Peichel CL, Blackman BK, Nereng KS, Jonsson B, Schluter D, Kingsley DM. Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 2004, 428: 717–723.
- 102Chan YF, Marks ME, Jones FC, Villarreal G, Shapiro MD, Brady SD, Southwick AM, Absher DM, Grimwood J, Schmutz J, et al. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 2010, 327: 302–305.
